Infections of mucosal surfaces, such as the lung, intestine, nd urogenital tract, are the most common causes of infectious disease morbidity and mortality in all species. We seek to determine whether the recognition and processing efficiency of pathogens and commensals by mucosal dendritic cells (DCs) or other phagocytes control susceptibility to infection. We hypothesize that susceptibility to mucosal infection depends on mucosal Toll-like receptor (TLR)-mediated recognition, differential cytokine production, and intracellular survival and spread of microbes within trafficking antigen-presenting cells (APCs). To test this hypothesis, we will identify the component(s) of the innate response that determine microbial survival or clearance. Our specific aims are to determine: 1) How the recognition of representative commensals and pathogens affects microbial survival and trafficking of mucosal antigen-presenting cells (DCs and macrophages). After nasal challenge, the commensal microorganisms Lactobacillus murinus and Streptococcus gordonii are hypothesized to be efficiently recognized by TLRs on mucosal APCs, phagocytosed, and killed, whereas the pathogens Streptococcus pyogenes and Porphyromonas gingivalis escape to remain localized or disseminate to distant sites. 2) The contribution of MyD88 and TRIF pathways in epithelial cells and antigen-presenting cells to local infection and systemic dissemination of commensal and pathogenic bacteria. We hypothesize that TLRs regulate the epithelial crossing of commensal and pathogenic bacteria by signaling through the MyD88 and TRIF pathways in epithelial cells and not in bone marrow-derived cells. 3) The efficiency of antigen presentation and the T-cell activation potential of dendritic cells and macrophages loaded with pathogens or commensals. We hypothesize that commensals are phagocytosed and killed, activating local APCs and presenting antigen to T-helper cells, whereas pathogens survive in DCs, dampening antigen presentation as DCs migrate to regional lymphoid organs and spleen to activate T cells. 4) The cytokine profiles of mucosal antigen-presenting cells after uptake of representative commensal or pathogenic bacteria. We hypothesize that pathogens induce phagocytic APCs in nasal-associated lymphoid tissue to express cytokines driving Th1 and Th17 differentiation, while commensals induce a Th1 and Th2 response. This project will elucidate the link between mucosal microbial phagocytosis and infectivity, clarifying the difference between commensal and pathogenic microorganisms. How the immune system recognizes and manages pathogens is crucial to the outcome of infectious diseases. Ultimately understanding immune discrimination between commensal and pathogenic bacteria will be important to mucosal vaccine development and human health.